ARMC1 shuttling regulates cellular mitochondrial distribution

Mitochondria are platforms for important processes including mitochondrial fusion and fission, protein and lipid transport, cytoskeletal trafficking, and the activation of mitophagy, apoptosis, and innate immune responses. How cells regulate the assembly of protein complexes at the mitochondrial surface to control these dynamic functions is incompletely understood. Here, we show that ARMC1 shuttles between the cytosol and distinct mitochondrial complexes. The assembly of ARMC1 with Miro, MTFR, and TMEM11 links together mitochondrial trafficking and shaping activities and is essential for MTFR stability. In another complex, ARMC1 engages, via MTCH2, DNAJC11, which facilitates ARMC1 recycling back into the cytosol. Disrupting the balance of ARMC1 between these complexes leads to aberrant cellular mitochondrial distributions. Thus, the stability and function of the Miro-MTFR complex is regulated by ARMC1, whose mito-cytoplasmic shuttling via DNAJC11 tunes mitochondrial dynamics. Our findings provide a paradigm for protein complex regulation through the spatial control of a linchpin subunit.